1. Field
The present disclosure relates generally to the fields of medicine, oncology and cancer diagnostics. More particularly, the disclosure provides methods, compositions and kits for diagnosing various neoplastic diseases, especially at early, asymptomatic or metastatic stages. Even more particularly, it concerns diagnostic methods for the early detection of cancer by quantifying phosphatidylserine (PS)-expressing tumor-derived cancer exosomes in patient samples.
2. Description of Related Art
While established screening programs for breast, cervical and colorectal cancer can detect asymptomatic disease, most other cancers come to clinical attention only after symptom emergence. On rare exceptions, this period may still represent early-stage disease. For instance, early hematuria can be diagnostic for bladder cancer that is still in situ or stage 1 tumor. Similarly, skin cancers are often apparent to patients and family, leading to early clinical follow-up. This is not the case, however, for the majority of visceral malignancies (thoracic, abdominal, and pelvic), where most patients remain asymptomatic at potentially curable stages. Although a minority of these cases can be investigated with blood tests or superficial tissue sampling, most of these scenarios lead to costly, invasive, and potentially morbid procedures.
Additionally, the increasing use of highly sensitive imaging technologies has resulted in an epidemic of radiographic findings of unclear clinical significance. Because of this, many affected individuals face the uncertainty and psychosocial distress inherent to a “watch and wait” approach. For instance, the annual low-dose helical chest computed tomography (CT) scans performed in high-risk patient populations in the National Lung Cancer Screening Trial (NLST) were found to be “positive” in up to 40% of individuals assessed over a 2-year period. These positive screens necessitated subsequent evaluations that included diagnostic CT, PET-CT, bronchoscopy, and even thoracotomy. Ultimately, only 4% of these cases were found to have malignancies. Cystic lesions of the pancreas (that may have malignant potential) are common, and increase with age. Incidental cysts are identified in 14% of all patients and 40% of patients over the age of 70 undergoing cross-sectional imaging. With rapidly increasing use of CT and MRI technology in emergency departments and other clinical settings, these and other “incidentalomas” are becoming a major issue threatening the quality and cost-containment of healthcare delivery. Indeed, at least 8 different “incidentalomas” involving numerous organ systems (pituitary, thyroid, pulmonary, hepatic, pancreatic, adrenal, renal, and ovarian) have been described. These radiographic findings frequently lead to recommendations for additional imaging studies, contributing to escalating health care costs and patient exposure to radiation (which has doubled in the past 15 years). These clinical events have become sufficiently common and problematic that the American College of Radiology has issued multiple white papers. Moreover, considerable psychosocial distress occurs while waiting for imaging follow-up notification and with false positive findings (40% of these experiences have been described as “very scary” or “the scariest moment of my life”). Nevertheless, Americans remain eager to participate in screening and imaging opportunities: Whole-body MRI and MRA, increasingly popular in population-based research, leads to detection of unexpected findings in 68% of otherwise healthy adults requiring further imaging or surveillance. Further complicating this issue is the recent phenomenon of electronic patient portals, where patients can view results of their diagnostic studies before their physicians have an opportunity to place them in context and provide counseling.
Therefore, there remains in the art a need for new and improved methods of diagnosing cancer that will be sufficiently sensitive to detect early stage disease and metastasis with a high degree of accuracy and reliability. The identification of a highly specific biomarker for all cancers would be an important advance, particularly a circulating blood biomarker that could be obtained with minimally invasive techniques. The field would particularly benefit from simple, cost-effective and reproducible methods to detect and quantify such a pan tumor biomarker that would clearly distinguish it from normal samples. Such a biomarker would significantly shorten the time to cancer diagnosis, resulting in earlier treatment and significantly better outcomes.